We previously developed cell-based
vaccines as
therapeutics for metastatic
cancers. The
vaccines were aimed at activating type I CD4(+)T cells and consisted of
tumor cells transfected with genes encoding syngeneic MHC class II and CD80 costimulatory molecules, and lacking the MHC II-associated
invariant chain. The
vaccines showed some efficacy in mice with
sarcoma,
melanoma, and
breast cancer and activated MHC class II syngeneic T cells from breast, lung, and
melanoma patients. During the course of the
vaccine studies, we observed that CD80 not only costimulated naïve T cells, but also bound to PD-L1 and prevented
tumor cell-expressed PD-L1 from binding to its
receptor PD-1 on activated T cells. A soluble form of CD80 (CD80-Fc) had the same effect and sustained IFNγ production by both human and murine PD-1(+) activated T cells in the presence of PD-L1(+) human or mouse
tumor cells, respectively. In vitro studies with human
tumor cells indicated that CD80-Fc was more effective than
antibodies to either PD-1 or PD-L1 in sustaining T cell production of IFNγ. Additionally, in vivo studies with a murine
tumor demonstrated that CD80-Fc was more effective than
antibodies to PD-L1 in extending survival time. Studies with human T cells blocked for CD28 and with T cells from CD28 knockout mice demonstrated that CD80-Fc simultaneously inhibited PD-L1/PD-1-mediated immune suppression and delivered costimulatory signals to activated T cells, thereby amplifying T cell activation. These results suggest that CD80-Fc may be a useful monotherapy that minimizes PD-1 pathway immune suppression while simultaneously activating
tumor-reactive T cells.